The present invention relates to an improved process for the preparation of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, and polymorphs thereof, the compound of formula-1 is further represented by the following structural formula:
Legal claims defining the scope of protection, as filed with the USPTO.
. A process for the preparation of amorphous form of Eluxadoline, comprising:
. The process according to, wherein the obtained amorphous form of Eluxadoline is characterized by its powder x-ray diffraction pattern as illustrated in.
. The process according to, wherein providing a solution of Eluxdoline 2-butanol solvate in step-a) is carried out by dissolving Eluxadoline 2-butanol solvate in a solvent at a temperature ranging from 25° C. to reflux temperature of the solvent used therein.
. The process according to, wherein the solvent used in step-a) is selected from alcohol solvents, nitrile solvents, hydrocarbon solvents, ketone solvents, ester solvents, water or mixture thereof.
. The process according to, wherein isolating the amorphous form of Eluxadoline in step-b) is by cooling, decantation, filtration by gravity or suction, centrifugation, adding to solvent to make slurry followed by filtration.
Complete technical specification and implementation details from the patent document.
This application is a national phase application under 35 U.S.C. § 371 of International Application Number PCT/IN2017/000098, filed on May 2, 2017, which claims priority to Indian Patent Application Numbers 201641015345 filed on May 3, 2016; 201641023195 filed on Jul. 6, 2016; 201741002480 filed on Jan. 23, 2017; and 201741002481 filed on Jan. 23, 2017; the disclosures of all of which are hereby incorporated by reference in their entirety.
The present invention relates to an improved process for the preparation of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, represented by the following structural formula:
The present invention also relates to novel crystalline forms and amorphous solid dispersions of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1.
Further, the present invention also relates to acid addition salts of (S)-methyl-2-methoxy-5-(((1-(4-phenyl-1H-imidazol-2-yl)ethyl)amino)methyl)benzoate compound of general formula-4.
5-[[[(2S)-2-Amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid known as Eluxadoline and is approved by USFDA under the brand name VIBERZI for the treatment of irritable bowel syndrome with diarrhea. Irritable bowel syndrome is a long-term disorder of the gut with pain or discomfort in the abdomen (belly), bloating and altered bowel habit. European Commission granted a marketing authorization for Eluxadoline (Truberzi) on 19 Sep. 2016.
5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid and process for its preparation was first disclosed in U.S. Pat. No. 7,741,356 B2 herein after referred as US'356 B2.
U.S. Pat. No. 7,994,206 B2 discloses the process for the preparation of Eluxadoline by treating boc protected Eluxadoline with hydrochloric acid to provide Eluxadoline hydrochloride, which is further treated with sodium hydroxide to provide Eluxadoline with low yield and purity. The said process suffers from several drawbacks such as cumbersome workup, compound of formula-1 is obtained as gummy semi-solid which is difficult to isolate and requires tedious purifications and finally provide compound of formula-1 with low yield.
In view of the above drawbacks, there is an unmet need to develop cost-effective, environmental friendly and commercially viable process for the preparation of Eluxadoline compound of formula-1 with high yield and purity.
U.S. Pat. No. 8,691,860 B2 discloses crystalline form-α of 5-[[[(2S)-2-amino-3-[4-(amino carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino] methyl]-2-methoxybenzoic acid compound of formula-1.
U.S. Pat. No. 7,994,206 B2 discloses crystalline form-β of 5-[[[(2S)-2-amino-3-[4-(amino carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1.
U.S. Pat. No. 8,609,865 B2 discloses process for the preparation of crystalline form-α and form-β of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino] methyl]-2-methoxybenzoic acid compound of formula-1.
IPCOM000245114D publication discloses crystalline forms of methyl 5-(((2S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl) propanamido)methyl)-2-methoxybenzoate dihydrochloride.
The said US'356 B2 discloses hydrochloric acid salt of 5-[[[(2S)-2-amino-3-[4-(amino carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1a but, does not have any information about the free base of compound of formula-1.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.
The first aspect of the present invention is to provide an improved process for the preparation of amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1.
The second aspect of the present invention is to provide 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid 2-butanol solvate compound of formula-1 and process for its preparation.
The third aspect of the present invention is to provide a novel, accurate and sensitive HPLC method for analyzing 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 and its intermediates.
The fourth aspect of the present invention is to provide crystalline form of 5-(((2S)-2-((tert-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxy benzoate lithium salt compound of formula-5b, herein after designated as form-S1 and process for its preparation.
The fifth aspect of the present invention is to provide 5-(((2S)-2-((tert-butoxy carbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxy benzoate sodium salt compound of formula-5a.
The sixth aspect of the present invention is to provide a process for the preparation of amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxo propyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1.
The seventh aspect of the present invention is to provide a novel crystalline form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 herein after designated as form-N and process for its preparation.
The eighth aspect of the present invention is to provide a novel crystalline form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 herein after designated as form-M1 and process for its preparation.
The ninth aspect of the present invention is to provide a novel crystalline form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 herein after designated as form-M2 and process for its preparation.
The tenth aspect of the present invention is to provide acid addition salts of (S)-methyl-2-methoxy-5-(((1-(4-phenyl-1H-imidazol-2-yl)ethyl)amino)methyl)benzoate compound of formula-2 and process for its preparation.
The eleventh aspect of the present invention is to provide the novel crystalline maleate salt of (S)-methyl-2-methoxy-5-(((1-(4-phenyl-1H-imidazol-2-yl)ethyl)amino)methyl) benzoate compound of formula-2a, herein after designated as form-M and process for its preparation.
The twelfth aspect of the present invention is to provide the novel crystalline oxalate salt of (S)-methyl-2-methoxy-5-(((1-(4-phenyl-1H-imidazol-2-yl)ethyl)amino)methyl) benzoate compound of formula-2b, herein after designated as form-S and process for its preparation.
The thirteenth aspect of the present invention relates to novel intermediate compound of formula-12, 13, 14, 15 which are useful in the preparation of compound of formula-1.
The fourteenth aspect of the present invention is to provide novel process for the preparation of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1.
The fifteenth aspect of the present invention is to provide an improved process for the preparation of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1.
The sixteenth aspect of the present invention is to provide novel crystalline form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, herein after designated as Form-N1 and its preparation thereof.
The seventeenth aspect of the present invention is to provide novel crystalline form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, herein after designated as Form-N2 and its preparation thereof.
The eighteenth aspect of the present invention is to provide novel crystalline form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, herein after designated as Form-N3 and its preparation thereof.
The nineteenth aspect of the present invention is to provide amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with one or more pharmaceutical acceptable carrier and process for their preparation.
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, propylene glycol, 2-methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, anisole, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
The term “suitable base” used herein the present invention until unless specified is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as potassium hydride, lithium hydride and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia; and organic bases such as triethyl amine, methyl amine, ethyl amine, 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo (4.3.0)non-5-ene (DBN), lithium dioisopropyl amide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropyl amine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethyl aminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methyl imidazole, 1,2,4-triazole, 1,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.
The suitable hydrochloric acid source is selected from HCl gas, aqueous HCl, dry HCl, ethyl acetate-HCl, IPA-HCl, ethanol-HCl, methanol-HCl.
The “coupling agent” is selected from N,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide HCl (EDC.HCl), alkyl or aryl chloroformates such as ethylchloro formate, benzylchloroformate, diphenylphosphoroazidate (DPPA), (Benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexa fluorophosphate, methanesulfonyl chloride and the like optionally in combination with 1-hydroxy-7-azatriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt), N-hydroxysuccinamide, N-hydroxysulfosuccinimide (Sulfo-NHS) or mixture thereof.
The first aspect of the present invention provides an improved process for the preparation of amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of following steps;
The preferred embodiment of the present invention provides an improved process for the preparation of amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of following steps;
In an embodiment of the present invention, the compound of formula-4 can also be treated with a suitable base such as alkali or alkaline earth metal hydroxide or carbonates or bicarbonates or alkoxides that can form alkali or alkaline earth metal salts of compound of formula-5.
In an embodiment of the present invention the compound of formula-5a can be treated with a suitable acid in a suitable solvent to provide acid addition salts of compound of formula-1.
U.S. Pat. No. 7,741,356 B2 discloses process for the preparation of 5-(((2S)-2-(tert-butoxycarbonylamino)-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxybenzoic acid herein after referred to as “2-methoxybenzoic acid” by, reacting methyl-5-(((2S)-2-((tert-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido) methyl)-2-methoxy benzoate compound of formula-4 with aqueous lithium hydroxide in the presence of tetrahydrofuran and methanol for longer hours and followed cumbersome work-up and tedious column chromatographic purification provides 2-methoxybenzoic acid with low yield.
The said process suffers from several draw backs such as utilizing multiple solvent system, lengthier reaction time and cumbersome work-up along with tedious column purification to isolate 2-methoxybenzoic acid with low yield. The said process also involves excess of solvents which leads to the generation of lot of spent solvents and solid waste which are difficult to dispose and which can lead to the pollution of the environment. Further, the said process increases the cost of the production and which is not recommended for commercial scale-up.
The present process is simple, eco-friendly and commercially viable, which involves lower mole ratio of lithium hydroxide in a single solvent and takes less time period for the completion of the reaction and further without any column purifications provides compound of formula-5a with high yield.
5-(((2S)-2-((tert-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxybenzoate sodium salt compound of formula-5a is having purity greater than 98% as measured by HPLC.
5-(((2S)-2-((tert-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxybenzoate sodium salt compound of formula-5a obtained according to the present invention is having Boc alcohol impurity; Boc diacid impurity; RS-Isomer, Boc isopropyl ester impurity, amine impurity, Boc ester impurity and amide impurity less than 0.05% as measured by HPLC.
U.S. Pat. No. 7,994,206 B2 involves process for the preparation of compound of formula-1 by, reacting 2-methoxybenzoic acid with concentrated hydrochloric acid in acetone to provide hydrochloric acid salt of compound of formula-1, which is further neutralized by treating with aqueous sodium hydroxide to provide compound of formula-1 with low yield and purity.
On repetition of the above process, i.e. neutralization of hydrochloric acid salt of compound of formula-1 with sodium hydroxide, the compound of formula-1 is isolated as gummy solid with low yield and purity. In order to isolate compound of formula-1 as a free solid, required multiple number of purifications and thereby making the process more uneconomical and not suitable for commercial scale-up.
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May 26, 2026
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